Risk factors and prognosis of malignant peritoneal mesothelioma with paraneoplastic syndrome

Background Malignant peritoneal mesothelioma (MPM) is a rare and highly aggressive tumor. Its clinical manifestations are diverse, and the symptoms are not specific. Some patients will develop paraneoplastic syndrome (PS) during the disease course. This study aims to analyze the risk factors of PS in patients with MPM and their impacts on prognosis. Methods The clinical data of MPM patients who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) at our center from June 2015 to May 2023 were retrospectively analyzed. MPM patients were divided into PS group and non-PS group according to the diagnostic criteria. Univariate and multivariate analyses were performed to explore the risk factors of PS in MPM patients, and to analyze the impact of PS on prognosis. Results There were 146 MPM patients in this study, including 60 patients (41.1%) with PS and 86 patients (58.9%) without PS. The highest incidence of PS was thrombocytosis (33.6%), followed by neoplastic fever (9.6%). Univariate analysis revealed 8 factors (P < 0.05) with statistically significant differences between the two groups: prior surgical scores, targeted therapy history, Karnofsky performance status score, preoperative carbohydrate antigen (CA) 125 level, vascular tumor embolus, peritoneal cancer index, completeness of cytoreduction (CC) score and intraoperative ascites. Multivariate analysis identified 3 independent factors associated with PS: preoperative CA 125 level, vascular tumor embolus, and CC score. Survival analysis demonstrated that MPM patients with PS had worse prognosis, although PS was not an independent prognostic factor. Conclusions PS is not rare in patients with MPM, and is independently associated with preoperative CA 125 level, vascular tumor embolus and CC score. PS often indicates advanced disease and poor prognosis.


Introduction
Malignant peritoneal mesothelioma (MPM) is a rare and highly aggressive tumor originating from peritoneal mesothelial cells, accounting for 7%-30% of all mesothelioma [1].In the past, MPM was mainly treated with conservative treatment such as chemotherapy and palliative surgery, but the prognosis was poor, with a median overall survival (OS) of less than 1 year [2].With the development of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), the median OS of MPM patients have significantly prolonged to 34 to 92 months [3].And now CRS + HIPEC has become the standard treatment in epithelioid MPM.
The clinical symptoms of MPM are nonspecific and usually include abdominal pain, bloating, weight loss, and abdominal mass, and a few may manifest as intestinal obstruction and microcirculatory hypercoagulable state [4].In addition, some patients may also develop a variety of paraneoplastic syndrome (PS), which has various manifestations and present particular difficulties in clinical practice, resulting in missed diagnosis and misdiagnosis [5].
PS is a rare disorder that usually has a complex clinical presentation and is not caused by direct tumor invasion or compression.It arises from tumor secretions of hormones, peptides or cytokines or from immune crossreactivity between malignant and healthy tissue.PS can involve various systems such as endocrine, nerve, skin, rheumatism, and blood.Furthermore, PS can be present before tumors, so timely diagnosis can help improve the prognosis of malignant diseases [6].
PS associated with MPM is rare, and only a few cases were reported.So, the aim of this study is to retrospectively analyze the clinical data of 146 patients with MPM, summarize the occurrence of PS related to MPM, explore the risk factors of PS, and analyze their impacts on prognosis.

Patients
The study was approved by the Medical Ethics Committee of Beijing Shijitan Hospital affiliated to Capital Medical University (2015-[28]), and all patients signed an informed consent form before treatment.From our prospectively established database on patients with peritoneal malignancy, we selected 146 MPM patients with complete clinical data who underwent CRS + HIPEC from June 2015 to May 2023.All enrolled patients met the inclusion and exclusion criteria of CRS + HIPEC [7].According to the PS diagnostic criteria, MPM patients were divided into PS group and non-PS group.

Diagnostic criteria for PS
The diagnosis of PS is difficult to define.It is usually determined by the exclusion method, which must exclude direct invasion or metastasis of tumors, and exclude infection, nutrition, metabolism, anti-tumor treatment and other abnormalities.The specific diagnostic criteria of PS in this study refer to multiple literatures [8][9][10][11].

Follow-up
Follow-up was conducted by outpatient visit or telephone interview, covering the following information: survival status, time and cause of death.The last followup was June 3, 2023, and the follow-up rate was 100%.
OS was defined as the interval between the date of CRS + HIPEC surgery at our hospital and the end of follow-up or the date of disease-related death.

Statistical analysis
BM SPSS Statistics for Windows, version 25.0 (IBM Corp., Armonk, NY, USA) was used for data analysis.Measurement data were presented as mean ± standard deviation (SD), and t test was used when the data were in accordance with normal distribution and homogeneity of variance.Enumeration data were presented as frequencies and analyzed using the χ2 and Fisher's exact tests.Univariate and Logistic regression analysis were used to analyze the risk factors of PS in MPM.Univariate and Cox regression analysis were used to analyze the effect of PS on the prognosis of MPM patients, with P < 0.05 considered as statistically significant.

Analyses on PS-related factors
Univariate analysis revealed the following 8 factors with statistically significant differences between the two groups (P < 0.05): PSS, targeted therapy history, KPS, preoperative CA 125 level, vascular tumor embolus, PCI, CC score and ascites.The above factors were included in binary Logistic regression analysis, which identified 3 factors independently associated with PS: preoperative CA 125 level, vascular tumor embolus and CC score (Table 4).

Perioperative chemotherapy
The timing and type of chemotherapy for MPM patients between the two groups were analyzed.Univariate analysis revealed statistically significant difference in postoperative intravenous (P = 0.003) and intraperitoneal (P = 0.010) chemotherapy between two groups, while there was no statistically significant difference in preoperative intravenous (P = 0.342) and intraperitoneal chemotherapy (P = 0.606) (Table 5).According to the number of chemotherapy regimens received by two groups separately (Table 6), we found that pemetrexed combined with platinum was the most used in both preoperative and postoperative intravenous chemotherapy.The most common preoperative intraperitoneal chemotherapy regimen in both groups was platinum monotherapy.There were slight differences between two groups in postoperative intraperitoneal chemotherapy, pemetrexed plus platinum was most common in the non-PS group, while cisplatin was most common in the PS group.
The above factors were incorporated into the Cox regression model for multivariate analysis, delineating the following 6 independent prognostic factors: KPS, preoperative CA 125 level, PCI, RBC transfusion, Ki-67 index and SAEs (Table 7).PS was not an independent prognostic factor in MPM.

One typical case presentation of MPM related PS
In March 2022, a 27-year-old male patient was diagnosed as MPM, with a disease history of abdominal distension and fever for 5 months.The abdominal and pelvic computed tomography (CT) examination showed peritoneal thickening and abdominal and pelvic effusion.Peritoneal biopsy showed that mesothelioma could not be excluded.
After admission, the patient continued to have lowgrade fever, fatigue, and general discomfort, with the highest temperature of 38.7℃.The related laboratory tests, such as blood and urine routine and culture, C-reactive protein, procalcitonin, ascites culture, and chest X-ray, showed no evidence of infection.After physical cooling, the patient could improve, so neoplastic fever was considered.On July 25, 2022, the patient received CRS + HIPEC and was diagnosed as epithelioid type of MPM.The patient's body temperature was maintained at 36-37 ℃ after surgery, and no fever recurred (Fig. 2A).
In addition, the platelet count of this patient was 766 × 10 9 /L (Upper limit of normal: 350 × 10 9 /L) when he first visited our hospital.The change curves of platelet and CA 125 were analyzed retrospectively (Fig. 2B,  C).CA 125 and platelet decreased after each anti-tumor treatment.CA 125 can help to judge the ascites formation and the degree of peritoneal cancer tumor burden, so the decrease of CA 125 indicates the decrease of tumor burden.The change trend of platelet was parallel to the fluctuation of CA 125, suggesting that thrombocytosis was closely related to tumor.By September 3, 2023, the OS of this patient after surgery was 13.47 months (Fig. 3).In conclusion, the case suggests that CRS + HIPEC is the key to treating the primary disease and reduce the tumor burden of MPM with PS.The effect of only symptomatic and supportive treatment for these patients is limited, and CRS + HIPEC as the core anti-tumor treatment should be performed in time.

Discussion
Among the 146 MPM patients included in this study, 41.1% of the patients developed PS during the disease course, with thrombocytosis (33.6%) and neoplastic fever (9.6%) being the most common.Three factors independently associated with PS were preoperative CA 125 level, vascular tumor embolus, and CC score.The median OS was 23.9 months.Multivariate survival analysis revealed that KPS, preoperative CA 125 level, PCI, RBC transfusion, Ki-67 index, and SAEs were independent prognostic factors for MPM patients.PS was not an independent prognostic factor in MPM.
This study found that PS in MPM was not rare, the incidence was 41.1%, and the most common was thrombocytosis (33.6%), although it was lower than the previous reports (83%) [25].The possible mechanism of MPM-related thrombocytosis is that mesothelioma cells persistently secrete interleukin-6, which stimulate thrombopoietin to induce thrombocytosis [25].Alhamadh et al. [12] pointed out that thrombocytosis is a surrogate marker for tumor aggressiveness and has been associated with poor survival.The second most common PS was neoplastic fever (9.6%).Hermann et al. [9] pointed out that almost any other cancer can cause neoplastic fever, which may be caused by a variety of pyrogen in the body, such as tumor necrosis, interleukin-2 secreted by activated macrophages, and prostaglandins synthesized by tumors.
The risk of PS in MPM patients with vascular tumor embolus was 2.791 times higher than that in patients without vascular tumor embolus.Han et al. [26] found that vascular tumor embolus is an important marker of tumor progression and is often an independent risk  factor for the prognosis of malignant tumors.In addition, the risk of PS in MPM patients with increased preoperative CA 125 is 2.921 times higher than that in patients with normal preoperative CA 125.The level of CA 125 is parallel to the growth and decline of the tumor [5].Therefore, the above studies suggest that MPM with PS often indicates that the primary tumor is at the advanced stage and predicts a large tumor burden and poor prognosis.This was consistent with a much higher proportion of PCI > 20 in the PS group (75.0%) than in the non-PS group (59.3%), which also determined that MPM with PS was more likely to have incomplete cytoreduction (CC 2-3: 63.3% in PS group vs. 32.6% in non-PS group).We also analyzed the timing and type of chemotherapy between PS and non-PS groups, and discovered that the rate of postoperative chemotherapy was higher in the non-PS group than in the PS group, which may be related to the higher postoperative mortality in the PS group.We also found that pemetrexed combined with platinum was the most used regimen during the perioperative period of MPM patients, as consensus suggests.
At present, there is no consensus on the prognostic impacts of PS in cancer patients.Bilynsky et al. [11] pointed out that PS could not predict the treatment outcome of the underlying malignancy.However, Agarwala [10] pointed out that the severity of the syndrome may parallel the activity of the associated tumor and in some instances can be used to follow the clinical course of the disease.In this study, univariate analysis showed that the median OS in non-PS group was 30.7 months, which was significantly longer than that in PS group (14.0 months) (P = 0.016).Cox regression results showed that KPS, preoperative CA 125 level, PCI, RBC transfusion, Ki-67 index, and SAEs were independent prognostic factors for MPM patients, which was similar to previous studies [27].However, PS was not included in the above independent prognostic factors, which may indicate that timely and standardized treatment may reduce the adverse effects of PS on MPM patients.Therefore, it is expected to enhance the awareness of MPM-related PS, improve early diagnosis and treatment, could help further improve the survival of patients, and turn the current adverse prognostic factors into "favorable factors".
There are some limitations in this study.Clinicians have inadequate understanding of PS, incomplete history collection, incomplete examination, and one-sided analysis confined to specialist diagnosis, which leads to the neglect of many abnormal symptoms.In addition, this was a single-center study, the sample size is limited, and the relevant results could not be thoroughly investigated.It is necessary to expand the sample size and include multi-center studies for further verification.

Conclusion
PS in MPM is not rare, and often indicates that the primary tumor is at the advanced stage.MPM patients with PS have a large tumor burden and high surgical difficulty, leading to poor prognosis.Therefore, improving the understanding of MPM-related PS, early detection, early diagnosis, and early treatment are the key to improving the prognosis of patients.

Fig. 1
Fig. 1 Survival analysis.A, Overall survival analysis of all patients.B, Survival curve analysis of non-PS group and PS group

Table 1
The distribution and incidence of PS in this study

Table 2
Major clinicopathological characteristics of MPM patients between PS and non-PS groupsMPM malignant peritoneal mesothelioma, PS paraneoplastic syndrome, BMI body mass index, KPS Karnofsky performance status score

Table 3
Major CRS + HIPEC characteristics of MPM patients between PS and non-PS groupsCRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy, MPM malignant peritoneal mesothelioma, PS paraneoplastic syndrome, PCI peritoneal cancer index, CC completeness of cytoreduction, RBC red blood cells

Table 4
Multivariate analysis of MPM patients between PS and non-PS groupsMPM malignant peritoneal mesothelioma, PS paraneoplastic syndrome, OR odds ratio, CI confidence interval

Table 5
Timing of chemotherapy of MPM patients between PS and non-PS groupsMPM malignant peritoneal mesothelioma, PS paraneoplastic syndrome